Recognition of the Activated States of Gα13 by the rgRGS Domain of PDZRhoGEF

Chen, James Z.; Singer, William D.; Danesh, Shahab M.; Sternweis, Paul C.; Sprang, Stephen R.

doi:10.1016/j.str.2008.07.009

Cited by 47 publications

(131 citation statements)

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“…Recent crystal structures of complexes between a different G␣ 13 chimera (all but the N-terminal helix was native to G␣ 13 ) and the PDZ-RhoGEF rgRGS domain recapitulate the major findings of the G␣ 13/i1 -p115RhoGEF complex (Chen et al, 2008). As before, the N-terminal motif of the RhoGEF anchors to the ␣-helical domain of G␣ 13 using an IIG sequence motif and interacts with the switch regions (Fig.…”

Section: Heterotrimeric G Protein-regulated Rhogefs 115supporting

confidence: 64%

“…This conformational change lowers the affinity of G␣ for G␤␥ but increases its affinity for effectors. Upon binding GTP, a shallow hydrophobic canyon is created between switch II and the ␣3 helix of G␣ that is used for binding all the effectors that have been structurally characterized thus far (Tesmer et al, 1997b(Tesmer et al, , 2005Slep et al, 2001;Chen et al, 2005Chen et al, , 2008Lutz et al, 2007). There is sufficient variability in the residues that line the perimeter of this effector docking site to explain the exquisite specificity of G␣ for its downstream targets.…”

Section: Introductionmentioning

confidence: 99%

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Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Aittaleb

Boguth

Tesmer³

2009

Mol Pharmacol

137

145

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Activation of certain classes of G protein-coupled receptors (GPCRs) can lead to alterations in the actin cytoskeleton, gene transcription, cell transformation, and other processes that are known to be regulated by Rho family small-molecular-weight GTPases. Although these responses can occur indirectly via cross-talk from canonical heterotrimeric G protein cascades, it has recently been demonstrated that Dbl family Rho guanine nucleotide exchange factors (RhoGEFs) can serve as the direct downstream effectors of heterotrimeric G proteins. Heterotrimeric G␣ 12/13 , G␣ q , and G␤␥ subunits are each now known to directly bind and regulate RhoGEFs. Atomic structures have recently been determined for several of these RhoGEFs and their G protein complexes, providing fresh insight into the molecular mechanisms of signal transduction between GPCRs and small molecular weight G proteins. This review covers what is currently known about the structure, function, and regulation of these recently recognized effectors of heterotrimeric G proteins.Heterotrimeric G proteins are master regulators of cell homeostasis. By coordinating signaling between the ϳ800 G protein-coupled receptors (GPCRs) in the human genome and a relatively small handful of effector enzymes and channels in the cell, they control processes such as muscle contractility, glycogen metabolism, neurotransmission, and the concentration of intracellular ions. Their profound impact on nearly all cellular processes and their therapeutic potential have rendered them one of the most intensely studied signal transduction paradigms at the biochemical and molecular level (Sprang et al., 2007).When heterotrimeric G proteins are in their inactive, GDPbound state, they exist as an inert complex composed of ␣, ␤, and ␥ subunits (G␣␤␥). In this state, they are substrates for activated GPCRs, which catalyze nucleotide exchange on the ␣ subunit (G␣). When bound to GTP, G␣ releases the effector binding surface of the ␤ and ␥ heterodimer (G␤␥) so that both G␣ and G␤␥ can interact with and modulate the activity of specific downstream enzymes and channels. The G␣ subunit has weak guanine nucleotide triphosphatase (GTPase) activity that slowly returns the G protein to its GDP-bound state. G␣⅐GDP then becomes resequestered by G␤␥. Beyond serving as conduits for extracellular signals, heterotrimeric G proteins contribute to the fidelity, duration, and amplitude of GPCR signaling. A given class of heterotrimeric G protein can typically recognize only a subset of GPCRs, and can only interact with one or a few downstream effector targets, ensuring the specificity of signaling from receptor to effector. The rate of GTP hydrolysis on G␣ dictates the length of time that its signal is in play, and this rate -bound conformation. The Ras-like domain is colored cyan, and the ␣-helical domain is gray. The three nucleotide-dependent switch regions (switch I-III) are red. The canonical effector docking site, a shallow canyon formed between switch II and the ␣3 helix, is indicated by the tr...

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Section: Heterotrimeric G Protein-regulated Rhogefs 115supporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Aittaleb

Boguth

Tesmer³

2009

Mol Pharmacol

137

145

View full text Add to dashboard Cite

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“…GTP-bound Ga 13 interacts with the RH domain of these large multidomain-containing GEFs. This interaction stimulates their GEF activity leading to activation of RhoA Kozasa et al, 1998;Chen et al, 2008). Thus, RH-RhoGEFs are primary candidates that may link GRPR stimulation to RhoA activation.…”

Section: Introductionmentioning

confidence: 99%

Gα₁₃/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration

et al. 2014

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Gastrin-releasing peptide receptor (GRPR) is ectopically expressed in over 60% of colon cancers. GRPR expression has been correlated with increased colon cancer cell migration. However, the signaling pathway by which GRPR activation leads to increased cancer cell migration is not well understood. We set out to molecularly dissect the GRPR signaling pathways that control colon cancer cell migration through regulation of small GTPase RhoA. Our results show that GRP stimulation activates RhoA predominantly through G13 heterotrimeric G-protein signaling. We also demonstrate that postsynaptic density 95/disk-large/ZO-1 (PDZ)-RhoGEF (PRG), a member of regulator of G-protein signaling (RGS)-homology domain (RH) containing guanine nucleotide exchange factors (RH-RhoGEFs), is the predominant activator of RhoA downstream of GRPR. We found that PRG is required for GRP-stimulated colon cancer cell migration, through activation of RhoA-Rhoassociated kinase (ROCK) signaling axis. In addition, PRG-RhoA-ROCK pathway also contributes to cyclo-oxygenase isoform 2 (Cox-2) expression. Increased Cox-2 expression is correlated with increased production of prostaglandin-E 2 (PGE 2 ), and Cox-2-PGE 2 signaling contributes to total GRPR-mediated cancer cell migration. Our analysis reveals that PRG is overexpressed in colon cancer cell lines. Overall, our results have uncovered a key mechanism for GRPR-regulated colon cancer cell migration through the Ga 13 -PRG-RhoA-ROCK pathway.

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“…In animals, RGS proteins typically bind the switch region on their corresponding Gα proteins (60)(61)(62)(63)(64). The reported GAP resistant phosphorylation sites on Gαz were all at N terminus nearby the switch region (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine phosphorylation switching of a G protein

Li¹,

Tunc‐Ozdemir²,

Urano

et al. 2018

Journal of Biological Chemistry

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Heterotrimeric G protein complexes are molecular switches relaying extracellular signals sensed by G protein-coupled receptors (GPCRs) to downstream targets in the cytoplasm, which effect cellular responses. In the plant heterotrimeric GTPase cycle, GTP hydrolysis, rather than nucleotide exchange, is the rate-limiting reaction and is accelerated by a receptor-like regulator of G signaling (RGS) protein. We hypothesized that posttranslational modification of the Gα subunit in the G-protein complex regulates the RGSdependent GTPase cycle. Our structural analyses identified an invariant phosphorylated tyrosine residue (Tyr-166 in the Arabidopsis Gα subunit AtGPA1) located in the intramolecular domain interface where nucleotide binding and hydrolysis occurs. We also identified a receptor-like kinase that phosphorylates AtGPA1 in a Tyr-166-dependent manner. Discrete molecular dynamics simulations predicted that phosphorylated Tyr-166 forms a salt bridge in this interface and potentially affects the RGS protein-accelerated GTPase cycle. Using a Tyr-166 phosphomimetic substitution, we found that the cognate RGS protein binds more tightly to the GDP-bound Gα substrate, consequently reducing its ability to accelerate GTPase activity. In conclusion, we propose that phosphorylation of Tyr-166 in AtGPA1 changes the binding pattern with AtRGS1 and thereby attenuates the steady-state rate of the GTPase cycle. We coin this newly identified mechanism "substrate phosphoswitching." __________________________________ http://www.jbc.org/cgi

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Recognition of the Activated States of Gα13 by the rgRGS Domain of PDZRhoGEF

Cited by 47 publications

References 50 publications

Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Gα₁₃/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration

Tyrosine phosphorylation switching of a G protein

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Recognition of the Activated States of Gα13 by the rgRGS Domain of PDZRhoGEF

Cited by 47 publications

References 50 publications

Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors

Gα13/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration

Tyrosine phosphorylation switching of a G protein

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Gα₁₃/PDZ-RhoGEF/RhoA Signaling Is Essential for Gastrin-Releasing Peptide Receptor–Mediated Colon Cancer Cell Migration